Project Summary/Abstract There are over 10,000 new cases of SCI each year in the USA. The direct cost to society is over $8 billion each year. Despite best maximal therapy, recovery is limited with most patients having severe impairment and disability. The long-term goal of this project is to investigate the effectiveness of magnetic brain stimulation to augment behavioral gains after motor training in SCI patients. We have developed a model of activity dependent plasticity of the motor lower limb that will be used to study the effects of magnetic brain stimulation on the learning of a skilled motor task. Using this model we plan to examine two potential critical influences on the effect of brain stimulation on task learning. First we will evaluate the effects of homeostatic metaplasticity which refers to the impact a prior induction of plasticity has on the development of additional plasticity. Metaplasticity theory suggests that the effects of rehabilitation may be augmented if cortical plasticity is first reduced or downregulated using magnetic brain stimulation prior to motor training. Second we will evaluate the effects of Val66met polymorphisms involving a substitution of methionine for valine at codon 66 of the brain derived nerve growth factor (BDNF) gene. Recent studies indicate that activity dependent plasticity and homeostatic metaplasticity are significantly reduced in individuals with the Val66Met BDNF polymorphism. Therefore we plan to evaluate the effects priming inhibitory or excitatory magnetic brain stimulation has on skilled motor learning in the lower limb in healthy volunteers and in SCI patients. It is hoped that the results of this study will open up new vistas of understanding and therapeutic opportunities for rehabilitation of SCI individuals. Of the estimated 250,000 patients living in the United States with spinal cord injury, approximately 25% of these are Veterans. This number is likely to increase in the near future as a result of the Iraq war injuries. By including veterans with spinal cord injury in this study the results will be directly relevant to the large number of Veterans with spinal cord injury. PUBLIC HEALTH RELEVANCE: Project Narrative Spinal cord injury affects thousands of Americans each year and exerts a significant medical and socioeconomic burden on the health care system. Of the estimated 250,000 SCI patients living in the US, approximately 25% are Veterans. The study results will be directly relevant to the large number of Veterans with spinal cord injury. Therapeutic opportunities for SCI have been limited and new avenues of therapies are desperately needed to improve recovery after SCI. Recovery from SCI may be related to changes in brain structure and function called plasticity. In this project we hope to show that magnetic brain stimulation, known to change brain plasticity, is an effective way to facilitate or augment behavioral gains after rehabilitation. We also hope to elucidate the impact of specific genes implicated in cortical plasticity on motor training after injury and on the impact of brain stimulation on motor training. It is hoped that the results of this study will open up new vistas of understanding and therapeutic opportunities for rehabilitation of SCI individuals.